In our Phase I application, we proposed that blocking HTRA1 with antibodies might be an effective strategy for treating age related macular degeneration. We tested this hypothesis by a) generating monoclonal antibodies against HTRA1 and b) determining whether a monoclonal antibody would be effective in models of vascular eye disease. We have accomplished each of these aims, and are now in the position to move past proof-of- concept, and to fully characterize a lead monoclonal antibody, prioritize additional monoclonal antibodies, and humanize HTRA1 monoclonal antibodies. These are the steps required to develop and ultimately commercialize a HTRA1 monoclonal antibody as a therapeutic. The Specific Aims are;Aim 1: Identify and prioritize murine monoclonal antibodies for human HTRA1 Aim 2: Determine efficacy of murine monoclonal antibodies in animal models of AMD Aim 3: Humanization of HTRA1 monoclonal antibodies The major milestones for Phase I was the identification of a monoclonal antibody that recognizes HTRA1 and is effective in two animal models of ophthalmic vascular disease. This has been completed. The major milestone for the Phase II application is the identification and characterization of a HTRA1 monoclonal antibody that will be humanized for clinical use. Thus, the Phase II application is designed to produce a humanized HTRA1 that will support a FDA IND application. PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is the most common cause of visual impairment of the elderly in developed countries. Increased levels of a protein, HTRA1, is an important cause of AMD. Navigen will develop HTRA1 monoclonal antibodies for the treatment of AMD.